This invention relates to a benzoxazepine compound having an activity of lowering cholesterol-level and an activity of lowering triglyceride-level and useful for prophylaxis and therapy of hyperlipemia.
Abnormal increase of concentrations of lipids in plasma is called xe2x80x9chyperlipidemiaxe2x80x9d or xe2x80x9chyperlipemiaxe2x80x9d. Serum lipids include cholesterol (cholesterol ester, free cholesterol), phospholipid (lecithin, sphingomyelin, etc.), triglyceride (neutral fat), free fatty acid and other sterols. Increase of cholesterol and triglyceride is especially taken up as a problem from the clinical viewpoint [cf. Common Disease Series No.19 Koshikessho (hyperlipemia) compiled by Haruo Nakamura, published by Nankodo].
Therefore, adequate control of lipid concentration in blood is remarkably important for the prophylaxis or therapy of various diseases related to arteriosclerosis typically exemplified by ischemic heart disease and cerebral infarction. And, hypertriglyceridemia is considered to accompany pancreatic disorders.
As pharmaceutical compositions for lowering cholesterol in blood, attention has been drawn to those for controlling the biosynthesis of cholesterol, besides those of inhibiting its absorption by binding bile acid including, among others, cholestyramine, colestipol (for example, U.S. Pat. No. 4,027,009), and those of suppressing the intestinal absorption of cholesterol by inhibiting acyl coenzyme A cholesterol acyl transferase (ACAT) including melinamide (French Patent No.1476569). As pharmaceutical preparations for controlling the biosynthesis of cholesterol, lovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No. 4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which are capable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase, are provided for medicinal use. However, when HMG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are necessary for the living body, is also inhibited, so that occurrences of undesirable side effects to be caused thereby are feared.
While, as agents of lowering triglyceride, fibrinoic acid type compounds, for example, clofibrate (UK Patent 860303) and fenofibrate (German Patent 2250327), are provided for medicines, they are prohibited to use together with statin type compounds for the fear of causing liver-toxicity.
Squalene synthetase is an enzyme taking part in the essential stage of the cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene.
On the other hand, the compounds expected as inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase are disclosed in Journal of Medicinal Chemistry, Vol. 51, No. 10, pp. 1869-1871, 1988, JPA H1(1989)-213288, JPA H2(1990)-101088, JPA H2(1990)-235820, JPA H2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)-68591, JPA H3(1991)-148288, and U.S. Pat. No. 5,019,390, U.S. Pat. No. 5,135,935, WO9215579 and WO9309115.
Incidentally, hyperlipemia is also called xe2x80x9chyperlipoproteinemiaxe2x80x9d and is classified into the following six types (WHO classification) taking lipoproteins into consideration.
Type I: hyperchylomicronemia showing increase of chylomicrons,
Type IIa: hyperLDLemia (hypercholesterolemia) showing increase of low-density lipoprotein (LDL),
Type IIb: composite hyperlipemia showing increase of LDL and very-low-density lipoprotein (VLDL),
Type III: abnormal xcex2 lipoproteinemia showing the presence of xcex2 very-low-density lipoprotein (xcex2 VLDL),
Type IV: endogenous hypertriglycerolemia, and
Type V: mixed type hyperlipemia showing increase of VLDL and chylomicrons.
Through intensive investigations from the above viewpoints, the present inventors synthesized, for the first time, a 4,1-benzoxazepine compound with the characteristic feature having specific substituents at 1-, 3-, 5- and 7-positions, and found that this compound has unexpectedly excellent lipid-level lowering activity based on the specific chemical structure, thus accomplishing the present invention.
More specifically, the present invention relates to:
(1) a compound represented by the formula (I) 
wherein R stands for a lower alkyl group substituted by 1 to 3 hydroxy group which may be substituted, X stands for an optionally substituted carbamoyl group or an optionally substituted heterocyclic group having a deprotonatable hydrogen atom R1 stands for a lower alkyl group and W stands for a hydrogen atom, or a salt thereof,
(2) the compound of (1) defined above, wherein R is C1-6 alkyl which may have 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy,
(3) the compound of (1) defined above, wherein R is C3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy,
(4) the compound of (1) defined above, wherein R is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl or 3-acetoxy-2-acetoxymethyl-2-methylpropyl,
(5) the compound of (1) defined above, wherein R1 is methyl,
(6) the compound of (1) defined above, wherein W is chlorine atom,
(7) the compound of (1) defined above, wherein X is a carbamoyl group represented by the formula 
wherein R2 and R3 are independently
(i) hydrogen,
(ii) optionally substituted hydrocarbon group,
(iii) optionally substituted heterocyclic group, or
(iv) acyl group or R2 and R3 may form an optionally substituted 5 to 6 membered ring together with the adjacent nitrogen atom, said ring may contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to said nitrogen atom,
(8) the compound of (7) defined above, wherein R2 is hydrogen or C1-7 alkyl, R3 is
1) a hydrocarbon group selected from the group consisting of
(a) C1-7 alkyl,
(b) C3-7 cycloalkyl,
(c) C2-6 alkenyl,
(d) C6-10 aryl and
(e) C6-10 aryl-C1-4 alkyl,
xe2x80x83wherein each of said groups (a), (b) and (c) may have 1 to 4 substituents selected from the group consisting of
(i) carboxyl which may be esterified with C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(ii) phosphono group which may be mono- or di-substituted by C1-6 alkyl or C2-7 alkanoyloxy-C1-6 alkyl,
(iii) sulfo group,
(iv) sulfonamido which may be substituted by C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(v) hydroxyl group which may be alkylated with C1-3 alkyl,
(vi) sulfhydryl group which may be alkylated with C1-3 alkyl,
(vii) carbamoyl,
(viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, chlorine, fluorine, aminosulfonyl and amino which may be mono or di-substituted by C1-3 alkyl,
(ix) amino which may be mono- or di-substituted by C1-3 alkyl,
(x) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, 4-phenylpiperazinyl, 1,2,3,4-tetrahydroisoquinolin and phthalimido, each of said group may be substituted by C1-3 alkyl, benzyl or phenyl and
(xi) 5- to 6-membered heterocyclic group selected from the group consisting of pyridinyl, imidazolyl, indolyl and tetrazolyl,
xe2x80x83and each of said group (d) and (e) may have 1 to 4 substituents selected from the group consisting of
(i) carboxyl which may be esterified by C1-4 alkyl,
(ii) phosphono which may be mono- or di-substituted by C1-6 alkyl or C2-7 alkanoyloxy-C1-6 alkyl,
(iii) sulfo,
(iv) C1-4 alkylsulfonyl, C6-10 arylsulfonyl or C6-10 aryl-C1-4 alkylsulfonyl,
(v) sulfonamido which may be substituted by C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(vi) C1-3 alkyl group which may be substituted by carboxyl group optionally esterified with C1-4 alkyl, phosphono which may be mono- or di-substituted by C1-6 alkyl, sulfo or sulfonamido which may be substituted by C1-6 alkyl or C6-10 aryl-C1-4 alkyl and
(vii) halogen,
2) a heterocyclic group selected from the group consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl and 2,3-dihydro-3-thioxo-1,2,4-triazolyl or the salt thereof,
3) an acyl group selected from the group consisting of
(i) C2-7 alkanoyl which may be substituted by 1 to 2 halogen atoms,
(ii) C6-10 arylsulfonyl,
(iii) C1-4 alkylsulfonyl, and
(iv) C6-10 aryl-C1-4 alkylsulfonyl,
xe2x80x83each of said group (ii), (iii) and (iv) may have 1 to 4 substituents selected from the group consisting of C1-3 alkyl, C1-3 alkoxy and halogen,
xe2x80x83or R2 and R3 together with adjacent nitrogen form a 5-or 6- membered cyclic amino selected from the group consisting of piperazinyl, piperidyl, pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and thiomorpholinyl, each of said group may have 1 to 4 substituents selected from the group consisting of
(A) hydroxyl which may be substituted with C1-3 alkyl or C2-7 alkanoyl,
(B) carboxyl which may be substituted with C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(C) phosphono which may be mono- or di-substituted by C1-6 alkyl or C2-7 alkanoyloxy-C1-6 alkyl,
(D) sulfo,
(E) sulfonamide which may be substituted with C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(F) C1-6 alkyl or C2-5 alkenyl which may be substituted by
xe2x80x83(i) carboxyl group which may be esterified with C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
xe2x80x83(ii) phosphono group which may be mono- or di-substituted by C1-6 alkyl or C2-7 alkanoyloxy-C1-6 alkyl,
xe2x80x83(iii) sulfo group,
xe2x80x83(iv) sulfonamido which may be substituted by C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
xe2x80x83(v) hydroxyl group which may be alkylated with C1-3 alkyl or C2-7 alkanoyl,
xe2x80x83(vi) sulfhydryl group which may be alkylated with C1-3 alkyl,
xe2x80x83(vii) carbamoyl,
xe2x80x83(viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, aminosulfonyl and amino which may be substituted with C1-3 alkyl and
xe2x80x83(ix) amino which may be mono- or di-substituted by C1-3 alkyl, or
xe2x80x83(x) tetrazolyl,
(G) amino which may be mono- or di-substituted with C1-3 alkyl,
(H) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, and 4-phenyl- piperazinyl,
(I) cyano,
(J) carbamoyl,
(K) oxo,
(M) carbamoyl substituted with C1-4 alkylsulfonyl, C6-10 arylsulfonyl or C6-10 aryl-C1-4 alkylsulfonyl,
(L) heterocyclic group selected from tetrazolyl and 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl,
(N) sulfhydryl which may be alkylated with C1-3 alkyl,
(O) phenyl which may have 1 to 5 substituents selected from hydroxyl, halogen, aminosulfonyl and amino which may be substituted with C1-3 alkyl, or the salt thereof,
(9) the compound of (7) defined above, wherein R2 and R3 together with the adjacent nitrogen of the carbamoyl form a 5 to 6-membered ring selected from the group consisting of 1-piperazinyl, piperidyl, 1-pyrrolidinyl, 2-oxo-piperazinyl and 2,6-dioxo-piperazinyl, each of the said group may have 1 to 2 substituents of C1-6 alkyl which may be substituted by
(i) carboxyl which may be esterified with C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(ii) phosphono group which may be mono- or di-substituted by C1-6 alkyl or C2-7 alkanoyloxy-C1-6 alkyl,
(iii) sulfo group,
(iv) sulfonamido which may be substituted by C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(v) hydroxyl group which may be alkylated by C1-3 alkyl,
(vi) sulfhydryl which may be alkylated by C1-3 alkyl,
(vii) carbamoyl,
(viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, aminosulfonyl and amino which may be substituted with C1-3 alkyl,
(ix) amino which may be mono- or di-substituted by C1-3 alkyl, or
(x) tetrazolyl,
(10) the compound of (7) defined above, wherein R2 is hydrogen or C1-7 alkyl and R3 is C1-4 alkylsulfonyl,
(11) The compound of term (1) defined above, wherein the heterocyclic group represented by X is tetrazolyl, 4,5-dihydro-5-oxo-1,2 ,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl, or 2,3-dihydro-3-thioxo-1,2,4-triazolyl,
(12) the compound of (1) defined above, wherein R1 is methyl, W is chlorine atom, R is C3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is the carbamoyl group represented by a formula 
wherein R2xe2x80x2 is hydrogen or C1-7 alkyl and R3xe2x80x2 is C1-4 alkyl,
(13) the compound of (1) defined above, wherein R1 is methyl, W is chlorine atom, R is C3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is the carbamoyl group represented by a formula 
wherein Rxe2x80x2 is hydrogen or C1-7 alkyl and n is an integer from 1 to 5,
(14) the compound of (1) defined above, wherein R1 is methyl, W is chlorine atom, R is C3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is a carbamoyl group represented by the formula 
wherein Rxe2x80x3 is hydrogen or C1-4 alkyl,
(15) the compound of (1) defined above, wherein R1 is methyl, W is chlorine atom, R is C3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is tetrazolyl,
(16) the compound of (1) defined above, which is (3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, (3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-acetamide, or a salt thereof,
(17) the compound of (1) defined above, which is (3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, (3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5- (2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid, N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid, N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester, N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester or a salt thereof,
(18) the compound of (1) defined above, which is (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4, 1-benzoxazepine-2-one, (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl4,1-benzoxazepine-2-one, (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl4,1-benzoxazepine-2-one, (3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl)methyl4,1-benzoxazepine-2-one or a salt thereof,
(19) the compound of (1) defined above, which is (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1, -benzoxazepine-3-acetamide or the salt thereof,
(20) the compound of (1) defined above, wherein R stands for a lower alkyl group substituted by 1 to 3 hydroxy groups which may be substituted, X is carbamoyl group, which may have substituent(s) on the nitrogen atom of the carbamoyl group,
(1) hydrocarbon selected from the group consisting of
(a) C1-7 alkyl,
(b) C3-7 cycloalkyl,
(c) C2-6 alkenyl,
(d) C6-10 aryl and
(e) C7-14 arylalkyl (C6-10 aryl-C1-4 alkyl),
xe2x80x83wherein each of said groups (a), (b) and (c) may have 1 to 4 substituents selected from the group consisting of
(i) carboxyl which may be esterified with C1-6 alkyl or C7-10 arylalkyl (phenyl-C1-4 alkyl),
(ii) phosphono group,
(iii) sulfo group,
(iv) sulfonamido which may be substituted by C1-6 alkyl or C7-10 arylalkyl (phenyl-C1-4 alkyl),
(v) hydroxyl group which may be alkylated with C1-3 alkyl,
(vi) sulfhydryl group which may be alkylated with C1-3 alkyl,
(vii) carbamoyl,
(viii) phenyl which may have substituent(s) selected from the group consisting of hydroxyl, chlorine, fluorine, aminosulfonyl and amino which may be mono- or di-substituted by C1-3 alkyl,
(ix) amino which may be mono- or di-substituted by C1-3 alkyl,
(x) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and 4-phenylpiperazinyl, each of said group may be substituted by C1-3 alkyl, benzyl or phenyl and
(xi) 5- to 6-membered heterocyclic group selected from the group consisting of pyridinyl, imidazolyl, indolyl and tetrazolyl,
xe2x80x83and each of said group (d) and (e) may have 1 to 4 substituents selected from the group consisting of
(i) carboxyl which may be esterified by C1-4 alkyl,
(ii) phosphono,
(iii) sulfo,
(iv) sulfonamido which may be substituted by C1-6 alkyl or C7-10 arylalkyl (phenyl-C1-4 alkyl),
(v) C1-3 alkyl group which may be substituted by carboxyl group optionally esterified with C1-4 alkyl, phosphono, sulfo, or sulfonamido optionally substituted with C1-6 alkyl or C7-10 arylalkyl (phenyl-C1-4 alkyl), and
(vi) halogen,
(2) a heterocyclic group selected from the group consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl and 2,3-dihydro-3-thioxo-1,2,4-triazolyl,
(3) an acyl group selected from the group consisting of
(i) C2-7 alkanoyl which may be substituted by 1 to 2 halogen atoms,
(ii) C6-10 arylsulfonyl,
(iii) C1-4 alkylsulfonyl, and
(iv) C7-14 arylalkylsulfonyl (C6-10 aryl-C1-4 alkylsulfonyl),
xe2x80x83each of said group (ii), (iii) and (iv) may have 1 to 4 substituents selected from the group consisting of C1-3 alkyl, C1-3 alkoxy and halogen or
(4) cyclic amino carbonyl group, the cyclic amino group being selected from the group consisting of piperazinyl, piperidyl, pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and thiomorpholinyl, each of said group may have 1 to 4 substituents selected from the group consisting of
(i) hydroxyl,
(ii) carboxyl optionally esterified with C1-4 alkyl,
(iii) phosphono,
(iv) sulfo,
(v) sulfonamido optionally substituted with C1-6 alkyl or C7-10 arylalkyl (phenyl-C1-4 alkyl),
(vi) C1-3 alkyl or C2-5 alkenyl optionally substituted with (i), (ii), (iii), (iv) or (v) defined above,
(vii) amino optionally mono- or di-substituted with C1-3 alkyl,
(viii) cyclic amino group selected from piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and 4-phenylpiperazinyl,
(ix) cyano,
(x) carbamoyl,
(xi) oxo,
(xii) C1-3 alkoxy,
(xiii) heterocyclic group selected from tetrazolyl and 2,5-dihydro-5-oxo-2,4-oxadiazolyl, and
(xiv) carbamoyl substituted with C6-10 arylsulfonyl, C1-4 alkylsulfonyl or C7-10 arylalkylsulfonyl (phenyl-C1-4 alkylsulfonyl),
(21) a composition which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier,
(22) a pharmaceutical composition for inhibiting squalene synthetase, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier,
(23) a pharmaceutical composition for lowering the level of triglyceride, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier,
(24) a pharmaceutical composition for lowering the lipid-level, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier,
(25) a pharmaceutical composition for prophylaxis or therapy of hyperlipidaemia, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier,
(26) use of the compound of (1) defined above for manufacturing a pharmaceutical composition,
(27) use of the compound of (1) defined above for manufacturing a squalene synthetase inhibitor,
(28) use of the compound of (1) defined above for manufacturing a pharmaceutical composition for lowering the level of triglyceride,
(29) use of the compound of (1) defined above for manufacturing a pharmaceutical composition for lowering the lipid-level,
(30) use of the compound of (1) defined above for manufacturing a pharmaceutical composition for prophylaxis or therapy of hyperlipidaemia or coronary sclerosis,
(31) a method for inhibiting squalene synthetase in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal,
(32) a method for lowering the level of triglyceride in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal,
(33) a method for lowering the lipid-level in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal,
(34) a method for prophylaxis or therapy of hyperlipidaemia or coronary sclerosis in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal,
(35) a process for producing the compound or the salt thereof of (1) defined above, wherein X is an optionally substituted carbamoyl group, which comprises reacting a compound of the formula: 
wherein the symbols are the same as defined in term (1), or a salt thereof with a compound of the formula: 
wherein the symbols are the same:as defined in (7), or a salt thereof,
(36) the compound of (1) defined above, wherein R is 2,2-dimethyl-3-hydroxypropyl.
As the lower alkyl group shown by R, mention is made of C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl. Above all, C3-6 alkyl groups are preferable and C4-5 alkyl groups are more preferable. Especially, branched C4-5 alkyl groups such as isobutyl and neopentyl are most preferable. The substituent of lower alkyl group shown by R includes hydroxyl group which may be substituted with for example C2-20 alkanoyl, C1-7 alkyl and so on. Specifically, the substituent of lower alkyl group shown by R includes hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy. The number of the above substituents ranges from 1 to 3.
Examples of R include 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl and 3-acetoxy-2-acetoxymethyl-2-methylpropyl.
The xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d is represented by the formula 
The term xe2x80x9chydrocarbon groupxe2x80x9d described in the specification includes optionally substituted C1-7 straight-chain or branched alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1,1-dimethylethyl, n-phenyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, neopentyl, hexyl and heptyl), optionally substituted C3-7 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexylmethyl), optionally substituted C2-6 straight-chain or branched alkenyl groups (e.g. vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl), optionally substituted C6lo aryl groups (e.g. phenyl and naphthyl groups) and optionally substituted C6-10 aryl-C1-4 alkyl groups (e.g. benzyl, phenethyl and naphthylmethyl).
Substituents of xe2x80x9coptionally substituted C1-7 straight-chain or branched alkyl groups, optionally substituted C3-7 cycloalkyl groups and C2-6 straight-chain or branched alkenyl groupsxe2x80x9d are exemplified by carboxyl groups optionally esterified with C1-6 alkyl groups or C6-10 aryl-C1-4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl), phosphono group which may be mono- or di-substituted by C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl, or C2-7 alkanoyloxy-C1-6 alkyl such as acetyloxy methyl and pivaloyloxymethyl, sulfo group, sulfonamido group optionally substituted with C1-6 alkyl groups or C6-10 aryl-C1-4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl and benzyl), hydroxyl group and sulfhydryl group optionally alkylated with C1-3 alkyl groups (e.g. methyl, ethyl and propyl), carbamoyl group, phenyl group optionally substituted with 1 to 5 substituents [e.g. hydroxyl group, chlorine, fluorine, aminosulfonyl group, and amino group optionally substituted with C1-3 alkyl group (e.g. methyl, ethyl and propyl)], amino group optionally mono- or di-substituted with C1-3 alkyl groups (e.g. methyl, ethyl and propyl), cyclic amino groups which may further have a hetero atom selected from oxygen and sulfur as the ring-forming atoms, and which may be substituted by C1-3 alkyl, benzyl or phenyl, such as (piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, 4-phenylpiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, and phthalimido) and aromatic 5- to 6-membered heterocyclic groups containing 1 to 4 hetero-atoms selected from N, O and S (e.g. pyridinyl, imidazolyl, indolyl and tetrazolyl).
Further, examples of the substituents of C6-10 aryl groups and C6-10 aryl-C1-4 alkyl groups as the substituents of the optionally substituted amino groups forming the carbamoyl group of xe2x80x9coptionally substituted carbamoyl groupsxe2x80x9d shown by X include carboxyl groups optionally esterified with C1-4 alkyl groups (e.g. methyl, ethyl, propyl and t-butyl groups), phosphono group which may be mono- or di-substituted by C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl, or or C2-7 alkanoyloxy-C1-6 alkyl such as acetyloxy methyl and pivaloyloxymethyl, sulfo group, C1-4 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl and n-butylsulfonyl), C6-10 arylsulfonyl (e.g. phenylsulfonyl and naphthylsulfonyl) or C6-10 aryl-C1-4 alkylsulfonyl (e.g. benzylsulfonyl, phenethylsulfonyl and naphthylmethylsulfonyl), sulfonamido groups optionally substituted with C1-6 alkyl groups or C6-10 aryl-C1-4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl and benzyl), and C1-3 alkyl groups (e.g. methyl, ethyl, propyl and isopropyl) optionally substituted with (i) carboxyl groups optionally esterified with C1-4 alkyl group (e.g. methyl, ethyl, propyl and butyl), (ii) phosphono group which may be mono- or di-substituted by C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl, or C2-7 alkanoyloxy-C1-6 alkyl such as acetyloxymethyl and pivaloyloxymethyl, (iii) sulfo group and (iv) sulfonamido group optionally substituted with C1-6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl and hexyl) or C6-10 aryl-C1-4 alkyl (benzyl and phenethyl), and halogen (fluorine and chlorine).
The number of the substituents of xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d is 1 to 4, preferably 1 to 2.
Preferable examples of xe2x80x9coptionally substituted heterocyclic groupsxe2x80x9d described in the specification include heterocyclic groups having deprotonizable hydrogen atom optionally having one or two, preferably one, substituents of substituents such as oxo group and thioxo groups. As such heterocyclic groups, 5- to 6-membered heterocyclic groups consisting of 1 to 4, preferably 2 to 3, hetero-atoms selected from S, O and N are preferable. Specifically, tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl and 2,3-dihydro-3-thioxo-1,2,4-triazolyl are exemplified. Especially tetrazolyl is preferable.
The term xe2x80x9cacyl groupxe2x80x9d described in the specification refers to carboxylic acid acyl groups derived from carboxylic acid (C2-7 carboxylic acid acyl group e.g. acetyl, propionyl, butyryl and benzoyl) and optionally substituted C6-10 arylsulfonyl groups, C1-4 alkylsulfonyl groups and C6-10 aryl-C1-4 alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl, phenylsulfonyl, naphthylsulfonyl, phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl and naphthylethylsulfonyl). As the substituents of aryl-, alkyl- and arylalkylsulfonyl groups, mention is made of, for example, C1-3 alkyl (e.g. methyl, ethyl and propyl), C1-3 alkoxy (e.g. methoxy, ethoxy and propoxy), halogen (chlorine, fluorine and bromine), and 1 to 4, preferably 1 to 2, of them may optionally be substituted at any substitutable position.
The above-mentioned carboxylic acid acyl groups may optionally have 1 to 2 halogen atoms (chlorine, fluorine and bromine) as substituents.
The ring formed by R2 and R3 together with the adjacent nitrogen of the carbamoyl refers to optionally substituted 5- or 6-membered cyclic amino which may further have 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen as ring constituting atoms such as piperazinyl, piperidino, 1-pyrrolidinyl, 2-oxo-1-piperazinyl, 2,6-dioxo-1-piperazinyl, morpholinyl and thiomorpholinyl. These cyclic amino groups may optionally have 1 to 4, preferably 1 to 2, substituents. Examples of those substituents include hydroxyl group which may be substituted with C1-3 alkyl or C2-7 alkanoyl, carboxyl groups optionally esterified with a C1-4 alkyl group (e.g. methyl, ethyl, propyl or t-butyl group) or C6-10 aryl-C1-4 alkyl, phosphono group which may be mono- or di-substituted by C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl or C2-7 alkanoyloxy-C1-6 alkyl such as acetyloxymethyl and pivaloyloxymethyl, sulfo group and sulfonamido group optionally substituted with a C1-6 alkyl group or a C6-10 aryl-C1-4 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl or benzyl), C1-6 alkyl which may be substituted by
(i) carboxyl group which may be esterified with C1-6 alkyl, or C6-10 aryl-C1-4 alkyl,
(ii) phosphono group which may be mono- or di-substituted by C1-6 alkyl or C2-7 alkanoyloxy-C1-6 alkyl,
(iii) sulfo group,
(iv) sulfonamido which may be substituted by C1-6 alkyl or C6-10 aryl-C1-4 alkyl,
(v) hydroxyl group which may be alkylated with C1-3 alkyl or C2-7 alkanoyl,
(vi) sulfhydryl group which may be alkylated with C1-3 alkyl,
(vii) carbamoyl,
(viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, aminosulfonyl, amino which may be substituted with C1-3 alkyl and
(ix) amino which may be mono- or di-substituted by C1-3 alkyl, or
(x) tetrazolyl,
xe2x80x83and C2-5 alkenyl group (e.g. vinyl and allyl) which may be substituted by the same group selected among (i) to (x) as described above for substituents of C1-6 alkyl, amino groups optionally mono- or di-substituted with C1-3 alkyl groups, cyclic amino groups derived from 5- or 6-membered cyclic amine which may further have a hetero atom selected from nitrogen, sulfur and oxygen, and which may be substituted by C1-3 alkyl, benzyl or phenyl, such as piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and 4-phenylpiperazinyl, cyano group, carbamoyl group, oxo group, hetereocyclic groups optionally substituted with an oxo group or thioxo group having such a deprotonizable hydrogen atom as mentioned above (e.g. tetrazolyl and 2,5-dihydro-5-oxo-1,2,4-oxazolyl), carbamoyl groups substituted with C1-4 alkylsulfonyl, C6-10 arylsulfonyl and C6-10 aryl-C1-4 alkyl arylsulfonyl (methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, phenylsulfonyl and benzylsulfonyl), sulfhydryl which may be alkylated with C1-3 alkyl and phenyl which may have 1 to 5 substituents such as hydroxyl, halogen, aminosulfonyl and amino which may be substituted with C1-3 alkyl.
Examples of xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d shown by X include 
Examples of R2xe2x80x2 and Rxe2x80x2 include hydrogen and C1-7 alkyl. Among them, hydrogen is preferable.
Examples of R3xe2x80x2 include C1-4 alkyl such as methyl, ethyl, propyl and butyl.
Examples of C1-7 alkyl shown by R2, R2xe2x80x2, Rxe2x80x2 are the same as those described in xe2x80x9chydrocarbon groupxe2x80x9d.
Examples of Rxe2x80x3 include hydrogen and C1-4 alkyl. Among them, hydrogenis preferable.
Examples of C1-4 alkyl shown by R3xe2x80x2 and Rxe2x80x3 include methyl, ethyl, propyl, isopropyl, n-butyl and t-butyl.
Examples of n include 1, 2, 3, 4 and 5.
Preferable examples of optionally substituted heterocyclic groups having deprotonizable hydrogen atom, shown by X, include N-containing (preferably 1 to 4 nitrogen atoms) 5- to 6-membered heterocyclic groups having Brxc3x4nsted acid-like active proton, and those comprising 1 to 4, preferable 2 or 3, nitrogen atom, sulfur atom and oxygen atom, are preferable. As these substituents, mention is made of, for example, oxo group and thioxo group, and one or two, preferably one substituents may be present. As xe2x80x9coptionally substituted heterocyclic groups having deprotonizable hydrogen atomxe2x80x9d shown by X, mention is made of, for example, those exemplified as xe2x80x9coptionally substituted heterocyclic groupsxe2x80x9d as the substituents of the xe2x80x9coptionally substituted carbamoyl groupsxe2x80x9d shown by X, such as tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl.
As xe2x80x9clower alkyl groupsxe2x80x9d shown by R1, mention is made of C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl and hexyl. Among them, C1-3 alkyl groups are especially preferable. As R1, methyl group is especially preferable from the viewpoint of pharmacological activity.
As xe2x80x9chalogen atomsxe2x80x9d shown by W. mention is made of chlorine, fluorine, bromine and iodine atom. Among them, chlorine atom is especially preferable.
Specifically the following compounds are preferable:
(3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide,
(3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-acetamide,
(3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide,
(3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide,
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid,
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid,
N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester,
N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one,
(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one,
(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one,
(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one, (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, etc.
As salts of the compound (I), mention is made of pharmaceutically acceptable salts including inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate and methanesulfonate, metal salts such as sodium salt, potassium salt, calcium salt and aluminum salt, and basic salts such as triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt and cinchonine salt.
Hydrate and non-hydrate of compound (I) are also concluded in the scope of this invention.
In the compound represented by the formula (I) or salts thereof, asymmetric carbons exist at 3- and 5-positions, and trans-compounds, in which the substituent at 3-position and substituent at 5-position are faced to the reverse direction relative to the face of the 7-membered ring, is preferable. Especially, those in which the absolute configuration at 3-position is R-configuration and the absolute configuration at 5-position is S-configuration, are preferable.
While the compound represented by the above-mentioned formula (I) or salts thereof can be produced in accordance with, for example, methods disclosed in EPA567026, WO95/21834 [PCT application based on Japanese Patent Application H6(1994)-15531)], EPA645377 [application based on Japanese Patent Application H6(1994)-229159] and EPA645378 [application based on Japanese Patent Application H6(1994)-229160], or methods analogous to them, they can be produced also by, for example, the following methods.
More specifically, the compound of the formula (I) or a salt thereof can be produced, as shown by, for example, the following formula, by subjecting a corresponding 3-carboxymethyl compound (Ixe2x80x2) to condensation with a compound represented by the formula 
(R2 and R3 are defined above) 
[wherein each symbol is of the same meaning as defined above].
The compound (I) or a salt thereof can be produced by subjecting the compound represented by the formula (Ixe2x80x2) to condensation with the compound represented by the formula 
in a solvent, in the presence of a base when necessary, using a condensing agent. Examples of the solvent include hydrocarbons such as benzene, toluene, hexane and heptane, halogenic solvents such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, ethers such as ethyl ether, tetrahydrofuran and dioxane, acetonitrile and dimethylformamide. As the base, mention is made of triethylamine, 4-dimethylaminopyridine, triethylenediamine and tetramethylethylenediamine. As the condensing agent, mention is made of condensing agents employed for the synthesis of peptide, as exemplified by dicyclohexyl carbodiimide, diethyl cyanophosphate and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The compound represented by the formula 
is used in an amount ranging from 0.5 to 2 molar equivalents, preferably from 1 to 1.2 molar equivalent, relative to one mole of the compound shown by the formula (Ixe2x80x2), and the condensing agent is used in an amount ranging from 0.5 to 5 molar equivalents, preferably from 1 to 2 molar equivalents. The reaction temperature ranges from 0 to 100xc2x0 C., preferably from 20 to 50xc2x0 C. The reaction time ranges from 0.5 to 24 hours, preferably from about 1 to about 5 hours.
The compound (I) or a salt thereof with X as optionally substituted heterocyclic group having a deprotonizable hydrogen atom, by X, or the carbamoyl group substituted with the optionally substituted heterocyclic group having a deprotonizable hydrogen atom can be produced by converting the carboxyl group in the carbamoyl group substituted with carboxyl group or a substituent having carboxyl group, shown by X, into carboxylic acid amido, subjecting the carboxylic acid amido to dehydration to convert it further into cyano group, then converting the cyano group into the optionally substituted heterocyclic group having a deprotonatable hydrogen atom.
The above-mentioned conversion of carboxylic acid into carboxylic acid amido can be conducted in accordance with a per se known method. For example, a compound with carboxylic acid group is subjected to condensation with ammonium or ammonium chloride, when necessary in the presence of a base (e.g. triethylamine, dimethylaminobenzene, pyridine, potassium carbonate, sodium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate), using a condensing agent such as diethyl cyanophosphate or dicyclohexyl carbodiimide. As the solvent to be employed, mention is made of ethers such as diethyl ether, tetrahydrofuran or dioxane, halogen type solvents such as dichloromethane, chloroform or carbon tetrachloride, dimethylformamide and acetonitrile. In these solvents, relative to one mole of a compound having carboxyl group, 1 to 100, preferably about 1 to 5, molar equivalent of ammonia or ammonium chloride is used. The reaction temperature ranges from 0 to 100xc2x0 C., preferably from 0 to 50xc2x0 C., and the reaction time ranges from 0.1 to 24 hours, preferably from about 0.5 to about 5 hours.
For converting the carboxylic acid amido obtained thus above into cyano group, a compound having carboxylic acid amide is reacted with thionyl chloride in a solvent such as benzene, hexane, toluene or xylene to provide corresponding cyano compound.
The amount of thionyl chloride to be employed ranges, relative to 1 mole of the compound having carboxylic acid amido, from 1 to 10, preferably from 1 to 3, molar equivalents. The reaction temperature ranges from 50 to 200xc2x0 C., preferably from 70 to 150xc2x0 C. The reaction time ranges from 0.5 to 10 hours, preferably from about 0.5 to about 3 hours.
The above-mentioned conversion of cyano group into the optionally substituted heterocyclic group having a deprotonizable proton, e.g. tetrazole ring, can be performed by allowing a compound having cyano group to react with trimethylsilyl azide and dibutyltin (IV) oxide in a solvent such as benzene, hexane, toluene or xylene.
The amount of trimethylsilyl azide ranges, relative to 1 mole of the compound having cyano group, from 0.5 to 10, preferably from 1 to 3, molar equivalents, and the amount of dibutyltin (IV) oxide ranges from 0.01 to 3, preferably from about 0.05 to about 1, molar equivalents. The reaction temperature ranges from 0 to 200xc2x0 C., preferably from 50 to 150xc2x0 C. The reaction time ranges from 10 to 48 hours, preferably from 15 to 30 hours. Furthermore, conversion into, for example, 2,5-dihydro-5-oxo-1,2,4-oxadiazole ring can be performed by allowing hydroxylamine to react with the compound having cyano group, then by further carbonylating the resultant compound. Hydroxylamine (1 to 10, preferably 1 to 3, equivalents relative to 1 mole of the compound having cyano group) is allowed to react with the compound having cyano group in a solvent as exemplified by an alcohol solvent such as methanol, ethanol and propanol, dimethylformamide or acetonitrile, in the presence of a base such as sodium hydrogencarbonate, potassium hydrogencarbonate or potassium carbonate, at a temperature ranging from 30 to 150xc2x0 C., preferably from 50 to 100xc2x0 C., for 1 to 24 hours, preferably about 5 to about 10 hours. For carbonylation of the compound thus obtained, carbodiimide or phosgene, for example, is employed for the carbonylating agent, and, as the solvent, for example, ether type solvents such as diethyl ether, tetrahydrophosgene or dioxane, halogen type solvents such as dichloromethane or chloroform, and ethyl acetate are employed. The amount of the carbonylating agent ranges from 1 to 10, preferably 1 to 3 molar equivalents. The reaction temperature ranges from 30 to 150xc2x0 C., preferably from 50 to 100xc2x0 C., and the reaction time ranges from 1 to 24, preferably from about 3 to about 100 hours.
In the above-described reaction, the compound, in which the moiety corresponding to X of the synthetic intermediate is an esterified carboxyl group or an optically active carboxyl group, can be obtained by, for example, the method disclosed in WO095/21834. More specifically, at first, the corresponding racemic compound is obtained, which is then allowed to react with an optically active amino acid to form the amido bond, followed by subjecting the resultant compound to distillation, recrystallization and column chromatography to separate and purify the optically active isomer, and.then, the amido bond is again cleaved to give a (3R,5S) compound. Alternatively, by the cleaved reaction step shown by the formula: 
[wherein Piv stands for pivaloyl group, and other symbols are of the same meanings as defined above], enzymatic asymmetric hydrolysis is conducted to give an optically active isomer (S-configuration) of a benzyl alcohol derivative, then, using this optically active isomer as the starting material, in accordance with the method disclosed in EPA567026, to give the above-mentioned (3R,5S) of the compound (Ixe2x80x2) as defined above.
The compound represented by the formula (I) or a salt thereof in the present invention [hereinafter sometimes called the compound of the formula (I) or the compound (I)] is low in toxicity, has a squalene synthetase inhibiting activity and an activity of lowering the level of triglyceride, and, has an excellent activity of lowering the level of lipids, and is useful for the prophylaxis or therapy of hyperlipemia such as hypercholesteremia and hypertriglycerolemia of mammals (e.g. mouse, rat, rabbit, dog, cat, cow, pig and man), and also useful for the prophylaxis or therapy of renal diseases such as nephritis and nephropathy, arteriosclerosis, ischemic diseases, myocardial infarction, angina pectoris, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, diabetes mellitus (e.g. insulin resistant diabetes), pancreatic disorders and re-stenosis after percutaneous transluminal coronary angioplasty (PTCA).
The use of this invention is described in further detail as follows.
In view of the triglyceride-lowering activity, cholesterol-lowering activity and biological properties of the compound of the formula (1), the compound is especially useful for the therapy and prophylaxis of hyperlipemia, especially hypertriglycerolemia, hyperlipoproteinemia and hypercholesterolemia, and, atherosclerotic diseases caused therefrom, and, secondary diseases thereof, for example, coronary diseases, cerebral ischemia, intermittent claudication and gangrene.
For the therapy of these diseases, the compound of the general formula (1) can be used singly or in combination with any other medicinal ingredients containing a lipid-level lowering agent or a cholestrol-level lowering agent. In this case, these compounds are administered, preferably, orally, and, upon necessity, they may be administered as agents for rectal use in the form of suppository. Examples of medicinal agents which can be used in combination with thecompound (I) include fibrates [e.g. chlorofibrate, benzafibrate and gemfibrozil], nicotinic acid, its derivatives and analogues [e.g. acipimox and probucol], bile acid binding resins [e.g. cholestyramine and cholestypol], compounds inhibiting cholesterol absorption [e.g. sitosterol or neomycin], compounds controlling the biosynthesis of cholesterol [e.g. HMG-CoA reductase inhibiting agents such as lovastatin, simvastatin and pravastatin], and squalene epoxidase inhibiting agents [e.g. NB-598 and analogous compounds]. As further agents which can be used in combination with the compound (I), mention is made of, for example, oxidosqualene-lanosterolcyclases such as decalin derivatives, azadecalin derivatives and indane derivatives.
Additional, the compound of the general formula (I) is applicable to treatment of diseases related to hyperchylomicronemia, for example, acute pancreatitis. The mechanism of occurrence of pancreatitis has been considered that minute thrombus occurs in pancreatic blood capillary by the action of chylomicron or by strong topical irritation with the increase of free fatty acid produced by decomposition of triglyceride by pancreatic lipase due to hyperchylomicronemia. In view of the above, since the compound of the formula (I) of this invention has an activity of lowering the level of triglyceride, it can be used for the therapy of pancreatitis, and can be used for the therapy of pancreatitis singly or in combination with a known therapeutic method. For the therapy of this disease, the compound of the formula (I) can be administered orally or topically, or it can be used singly or in combination with a known active compound. As the agent which can be combined for this purpose, mention is made of, for example, aprotinin (trasylol), gabexate mesylate (FOY), nafamostat mesilate (Futhan), citicoline (nicholin) and urinastatin (miraclide). And, for the purpose of removing pain, antichlolinergic drugs, non-narcotic analgesics and narcotic drugs can also be used.
As further noticeable examples of diseases, to which the compound of the general formula (I) is applicable, mention is made of secondary hyperlipemia including, for example, diabetes mellitus, hypothyroidism, nephrotic syndrome or chronic renal failure. In many cases, these diseases cause hyperlipemia and the latter aggravates these diseases, causing a so-called vicious circle. Taking its lipid-level lowering activity into consideration, the compound of the general formula (I) is useful for the therapy and for preventing the aggravation of these diseases. For this purpose, the compound of the general formula (I) can be administered singly or in combination with examplary medicines set forth below.
Medicines for diabetes mellitus: kinedak, benfil, humulin, euglucon, glimicron, daonil, novorin, monotard, insulins, glucobay, dimelin, rastinon, bacilcon, deamiline S, iszilins;
Medicines for hypothyroidism: thyroid (thyreoid), levothyroxine sodium (thyradin S), liothyronine sodium (cylonine, cylomin);
Medicines for nephrotic syndrome: For the therapy using steroid as the first choice, use is made of, for example, predinisolone sodium succinate (predonine), prednisolone sodium succinate (predonine), methyl prednisolone sodium succinate (solu-medrol) and betamethasone (renderon). And, for anticoagulant therapy, use is made of antiplatelet medicines such as dipyridamole (persantine) and dilazep hydrochloride (comelian);
Medicines for chronic renal failure: A combination of diuretics [e.g. furosemide (lasix), bumetanide (lunetoron) and azosemide (diart)], hypotensive drugs (e.g. ACE inhibitors (enalapril maleate (renivace)) and Ca antagonists (Ca antagonistic drugs (maninhilone), xcex1-receptor blocking agents is administered, preferably, orally.
Another possible use of the compound of the general formula (I) of this invention is to inhibit the formation of thrombus. In view of the fact that the triglyceride level in blood is an positive correlation with the blood coagulation factor VII and intake of xcfx89-3 type fatty acid serves to lower the triglyceride level and, at the same time, the coagulation is inhibited, it has been considered that hypertriglycemia would promote the formation of thrombus. Since VLDL (very low density lipoprotein) of the patients suffering from hyperlipemia increased more strongly the secretion of plasminogen activator inhibitor from vascular endothelial cells than that of the patients suffering from normal lipemia, it is considered that triglyceride (hereinafter TG) acts to lower the fibrinolytic activity. Therefore, taking the TG lowering action, the compound of the general formula (I) can be effectively used for the prophylaxis and therapy of the formation of thrombus. The compound (I) can be administered singly or in combination with any of the following exemplary known therapeutic agents, preferably orally.
Medicines for prophylaxis and therapy of thrombus formation: blood coagulation inhibitors [e.g. heparin sodium, heparin calcium, warfarin calcium (warfarin)], thrombolytic agents [e.g. urokinase], antiplatelet agents [e.g. aspirin, sulfinpyrazolo(anturane), dipyridamole (persantine), acropidin (panaldin), cilostazol (pletaal)].
The compound (I) can be used orally or non-orally in the manner of injection, drip infusion, inhalation, rectal administration or topical administration, as it is or as a medicinal composition (e.g. powder, granule, tablet, pill, capsule, injection, syrup, emulsion, elixir, suspension and solution). In other words, at least one species of the compounds of this invention can be used singly or in combination with a pharmaceutically acceptable carrier (e.g. adjuvant, excipent, forming aid and/or diluent).
These pharmaceutical compositions can be prepared by a conventional method. These compositions can be prepared by usually mixing/kneading active components with an additive such as excipients, diluents and carriers. In the present specification, xe2x80x9cnon-oral administrationxe2x80x9d include subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or drip infusion. Injectable compositions, for example, a sterile injectable aqueous suspension or an oily suspension, can be prepared by a known method in the relevant field using a suitable dispersing agent or a moistening agent. The sterile injectable composition may be a solution or a suspension injectable under sterile conditions in a non-toxic diluent or a solvent administrable non-orally, for example, an aqueous solution. As a vehicle or a solvent which can be employed, mention is made of, for example, water, a Ringer solution and an isotonic aqueous saline solution. Further, a sterile non-volatile oil can also be employed as a common solvent or a suspending solvent. For this purpose, any non-volatile oil and fatty acid can also be employed, including natural or synthetic or semi-synthetic fatty oil or fatty acid as well as natural or synthetic or semi-synthetic mono- or di- or triglycerides.
The suppository for rectal use can be prepared by mixing the drug with a suitable non-irritable excipient, e.g. cocoa butter or polyethylene glycol which is solid at normal temperatures, liquid at temperatures in intestinal tube, and melts and release the drug in rectum.
As the solid dosage form for oral administration, mention is made of, for example, powder, granule, tablet, pill and capsule as mentioned above. The composition of such dosage form as above can be prepared by mixing and/or kneading a compound as the active component with at least one species of additives as exemplified by sucrose, lactose, cellulose, mannitol (D-mannitol), multitol, dextrin, starch (e.g. corn starch), microcrystalline cellulose, agar, alginates, chitins, chitosans, pectins, tragacanth gum, acacia, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. These compositions may optionally contain further additives, like in usual cases, for example, an inert diluent, a lubricant such as stearic acid and magnesium, a preservative such as parabens and sorbins, an antioxidant such as ascorbic acid, xcex1-tocopherol and cysteine, a disintegrant (e.g. floscaromelose sodium), a binder (e.g. hydroxypropyl cellulose), a thickening agent, a buffering agent, a sweetening agent, a flavoring agent and perfuming agent. Tablets and pills may optionally be prepared with enteric coating. As liquid preparations for oral administration, mention is made of, for example, a pharmaceutically acceptable emulsion, syrup, elixir, suspension and solution, and they may optionally contain an inert diluent such as water and, depending on necessity, an additive. These liquid compositions for oral administration can be prepared by a conventional method, for example, mixing the compound as the active component with an inert diluent and, upon necessity, any other additive.
The orally administrable compositions, while varying with the forms, are incorporated with usually 0.01 to 99 W %, preferably 0.1 to 90 W %, commonly 0.5 to 50% of the compound of this invention as the active component. The dose for a specific patient is determined, while taking into consideration age, body weight, general health conditions, sex, diet, the time of administration, the method of administration, secretion rate, combination of drugs, conditions of the disease then the patient is receiving the therapy and any other factors. A lipid level lowering agent such as a triglyceride level lowering agent comprising the compound (I) of this invention is relatively low in toxicity and can be safely used. Although the daily dose varies depending on the conditions and body weight of the patient, kinds of the compound, administration routes and any other factors, a daily dosage per adult human (about 60 kg body weight) in the case of, for example, oral administration for the prophylaxis and therapy of hyperlipemia ranges from about 1 to 500 mg, preferably from about 10 to 200 mg, of the effective component [compound (I)], and, in the case of a non-orally administrable composition, the daily dose range from about 0.1 to 100 mg, preferably from about 1 to 50 mg, commonly from about 1 to 20 mg in terms of the effective component. Within this range, no toxicity is observed at all.